Breast carcinoma is the most common form of cancer in women in the United States. Understanding the basic molecular markers during the transitions from normal cell to carcinoma to metastases will be helpful in treating the disease, but these processes still are poorly understood. Tumors arise from individual cells that undergo multiple genomic mutations. How do the initial mutations arise? Does the environment cause mutations or create an environment that promotes their accumulation? Extracellular matrix proteins, such as matrix metalloproteinases (MMPs), contribute to tumor progression. MMP-3/Stromelysin-1 has been shown to be involved in promoting mammary hyperplasia and cancer in mice; it is upregulated in human breast cancer, and its overexpression promotes genomic instability. In the research proposed, I will address the mechanism of genomic instability in cancer progression. The specific aims to be covered in this proposal are the following: (1) Examine the effect of MMP-3 on mammary stem cell differentiation. Recent work suggests that progenitor cells may be tumor precursors. (2) Determine if MMP-3 affects the rate of mutagenesis in mammary tumor development. (3) Examine effect of apoptosis on generating genomic instability and on MMP-3-dependent mammary tumor progression.